ISO 10993-4:2017/Amd 1
(Amendment)Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood — Amendment 1
Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood — Amendment 1
Évaluation biologique des dispositifs médicaux — Partie 4: Choix des essais pour les interactions avec le sang — Amendement 1
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International
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ISO 10993-4
Third edition
Biological evaluation of medical
2017-04
devices —
AMENDMENT 1
Part 4:
Selection of tests for interactions
with blood
AMENDMENT 1
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
AMENDEMENT 1
PROOF/ÉPREUVE
Reference number
ISO 10993-4:2017/Amd.1:2024(en) © ISO 2024
ISO 10993-4:2017/Amd.1:2024(en)
© ISO 2024
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on
the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address below
or ISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: +41 22 749 01 11
Email: copyright@iso.org
Website: www.iso.org
Published in Switzerland
PROOF/ÉPREUVE
ii
ISO 10993-4:2017/Amd.1:2024(en)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out through
ISO technical committees. Each member body interested in a subject for which a technical committee
has been established has the right to be represented on that committee. International organizations,
governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely
with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are described
in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types
of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the
ISO/IEC Directives, Part 2 (see www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent
rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
patent(s) which may be required to implement this document. However, implementers are cautioned that
this may not represent the latest information, which may be obtained from the patent database available at
www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions
related to conformity assessment, as well as information about ISO's adherence to the World Trade
Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical
devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee
CEN/TC 206, Biocompatibility of medical and dental materials and devices, in accordance with the Agreement
on technical cooperation between ISO and CEN (Vienna Agreement).
A list of all parts in the ISO 10993 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
PROOF/ÉPREUVE
iii
ISO 10993-4:2017/Amd.1:2024(en)
Biological evaluation of medical devices —
Part 4:
Selection of tests for interactions with blood
AMENDMENT 1
3.4
Replace “ISO/TR 10993-20” with “ISO/TS 10993-20” in Note 1 to entry.
5.2.2
Replace the subclause heading with:
5.2.2 External communicating devices indirectly contacting blood
Delete the bullet points “cannulae”, “cell savers”, “intravascular catheters” and “blood collection devices”.
Replace “blood and blood product” with “saline and/or therapeutics” as follows:
— devices for the storage and administration of either saline or therapeutics, or both (e.g. tubing and bags);
Add the bullet point “blood monitors with indirect blood contact” as the second bullet point.
5.2.3
Add “blood collection devices” as a second bullet point, “cannulae” as a fourth bullet point, “cell savers” as a
sixth bullet point and “devices for the storage and administration of blood and blood products (e.g. tubing
and bags)” as an eighth bullet point.
Delete “or indirect” in the third bullet point as follows:
— blood monitoring devices with direct blood contact;
6.1.2
Add the following text to the second paragraph after the sentence “Only direct or indirect blood-contacting
parts should be tested.”:
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(en)
For direct contact haemocompatibility testing (e.g. direct haemolysis, complement activation,
coagulation, platelet activation, haematology, in vitro or ex vivo thrombosis), testing should be conducted
using only the direct blood contacting components of the device to minimize interference of non-
direct blood contacting components on the results. For extract-based haemocompatibility testing (e.g.
indirect haemolysis), testing should be conducted using only the direct and indirect blood-contacting
components of the device. The test article shall be described and a justification shall be provided if the
test article includes device components that include different tissue contact than described above.
Replace the fourth paragraph with:
As many tests for haemocompatibility are recognized to be generally surface-contact dependent (e.g.
direct contact haemolysis, complement activation, coagulation, platelet activation, haematology, and
in vitro or ex vivo thrombosis), such tests do not apply to indirect contact applications. For externally
communicating medical devices or components that have indirect blood contact, only an indirect contact
haemolysis test is generally recommended.
6.1.4
Replace NOTE 1 with:
NOTE 1 Changes in the manufacturing process (e.g. change in manufacturer), the use of different manufacturing
aids that can affect the surface properties or the chemistry of the complete sterilized device can also impact
haemocompatibility.
6.1.6
Replace Table 1 with:
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(en)
PROOF/ÉPREUVE
Table 1 — Devices or device components and categories of appropriate testing for consideration
Test category
c
Thrombosis
Device examples Haemolysis
In vitro
In vivo or
a
ex vivo
d
Material-induced Mechanically-induced Coagulation Platelet activation Complement Haematology
e
External communicating devices indirectly contacting blood
Blood monitors with indirect blood contact X
Devices for storage and administration of saline and/or therapeutics
X
(e.g. tubing and bags), extension sets
b
External communicating devices directly contacting circulating blood
Blood collection devices X X X X
f
Blood administration sets and extension sets X X X X X
Catheters in place for less than 24 h (e.g. atherectomy devices, intra-
vascular ultrasound catheters, antegrade or retrograde coronary X X X X X
perfusion catheters, guide wires); cannulae
Catheters in place for more than 24 h (e.g. parenteral nutrition cathe-
X X X X X
ters, central venous catheters); cannulae
Cell savers X X X X
Devices for adsorption of specific substances from blood X X X X X
Donor and therapeutic aphaeresis equipment and cell separation
X X X X X
systems
Cardiopulmonary bypass system and components X X X X X X X
Haemodialysis or haemofiltration equipment X X X X X X X
Leukocyte removal filter X X X X X X
Percutaneous circulatory support devices X X X X X X X
Implant devices
Annuloplasty rings, mechanical heart valves X X X
Embolization devices X X
Endovascular grafts X X
Implantable defibrillator and cardioverter leads X X
Intra-aortic balloon pumps X X X
a
Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing might not be necessary if clinically relevant in vitro thrombosis testing is performed.
b
Some examples here may contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical haemolysis, thrombosis
and complement activation are not always necessary. For components with indirect blood contact, generally only an indirect contact haemolysis test is recommended.
c
It is recognized that coagulation, platelet and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo testing if scientifically
justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices.
d
Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.
e
Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.
f
For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.
ISO 10993-4:2017/Amd.1:2024(en)
PROOF/ÉPREUVE
Table 1 (continued)
Test category
c
Thrombosis
Device examples Haemolysis
In vitro
In vivo or
a
d ex vivo
Material-induced Mechanically-induced Coagulation Platelet activation Complement Haematology
Pacemaker leads X X
Prosthetic (synthetic) vascular grafts and patches, including arterio-
X X
venous shunts
Stents (vascular) X X
Tissue heart valves, vascular grafts and patches and AV shunts X X
Total artificial hearts X X X
Vena cava filters X X
Ventricular-assist devices X X X
a
Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing might not be necessary if clinically relevant in vitro thrombosis testing is performed.
b
Some examples here may contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical haemolysis, thrombosis
and complement activation are not always necessary. For components with indirect blood contact, generally only an indirect contact haemolysis test is recommended.
c
It is recognized that coagulation, platelet and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo testing if scientifically
justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices.
d
Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.
e
Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.
f
For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.
ISO 10993-4:2017/Amd.1:2024(en)
6.1.11
Delete “(see also ISO 10993-2)” at the end of the second paragraph.
6.1.12
Replace the paragraph with:
The use of antithrombotics in in vivo and ex vivo tests should be avoided unless the device is designed
to perform in their presence. Even if the device is designed to perform in their presence, the completion
of studies without antithrombotics can also be required in order to properly assess the thrombosis
risk to patients that cannot receive antithrombotics. The type and concentration of antithrombotic(s)
used influence(s) blood/device interactions and their selection shall be justified. Devices that are used
with antithrombotics should be assessed using them in the range of concentrations specified clinically
and/or described in the product IFU or other appropriate literature. Species differences should also be
considered when determining the appropriate level of antithrombotic(s).
Add the following NOTE at the end of this paragraph:
NOTE Antithrombotics can consist of any combination of either antiplatelet drugs (e.g. acetylsalicylic acid,
clopidogrel and glycoprotein IIb/IIIa receptor antagonists) or anticoagulants (e.g. unfractionated or low molecular
weight heparin, warfarin and direct thrombin inhibitors), or both.
6.1.14
Delete "see ISO 10993-2" and add the following NOTE after the paragraph:
NOTE For more information on animal welfare, see ISO 10993-2.
6.3.1
Replace “Alternatives to the latter may be feasible if validated.” with:
The use of blood older than 4 h may be feasible for certain tests, if validated alongside freshly obtained
blood or by other scientifically sound methods.
A.1.1
Delete “of non-contact-, externally communicating and implant devices” from the sentence as follows: “and a
list of tests for evaluating blood/device interactions.”
A.1.4
Replace the first sentence of the third paragraph with:
[43] [193][194][195][199][200][203]
The classical Chandler loop in vitro test model or modifications thereof are
examples of models used to test for general material or device haemocompatibility under physiological
and/or quasi-physiological flow conditions.
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(en)
Add the following sentence at the end of the third paragraph:
Recent publications that describe and apply alternative in vitro methods are References [243] to [249].
Clause A.3
Add “(or an alternative surface treatment intended to have anti-thrombotic prop
...
ISO 10993-4:2017/DAMPRF Amd 1:2024(E)
ISO/TC 194/WG 9
Secretariat: DIN
Amendment 1
Date: 2024-03-2310-16
Biological evaluation of medical devices — —
Part 4:
Selection of tests for interactions with blood — Amendment
AMENDMENT 1
Évaluation biologique des dispositifs médicaux —
Partie 4: Choix des essais pour les interactions avec le sang
AMENDEMENT 1
PROOF
ISO 10993-4:2017/PRF Amd 1(en)
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication
may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying,
or posting on the internet or an intranet, without prior written permission. Permission can be requested from either ISO
at the address below or ISO'sISO’s member body in the country of the requester.
ISO copyright office
CP 401 • Ch. de Blandonnet 8
CH-1214 Vernier, Geneva
Phone: + 41 22 749 01 11
Email: E-mail: copyright@iso.org
Website: www.iso.org
Published in Switzerland.
ii
ISO 10993-4:2017/PRF Amd 1(en)
Contents
iii
ISO 10993-4:2017/PRF Amd 1(en)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out through
ISO technical committees. Each member body interested in a subject for which a technical committee has been
established has the right to be represented on that committee. International organizations, governmental and
non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the
International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are described
in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of
ISO documents should be noted. This document was drafted in accordance with the editorial rules of the
ISO/IEC Directives, Part 2 (see www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent rights
in respect thereof. As of the date of publication of this document, ISO had not received notice of (a) patent(s)
which may be required to implement this document. However, implementers are cautioned that this may not
represent the latest information, which may be obtained from the patent database available at
www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions
related to conformity assessment, as well as information about ISO's adherence to the World Trade
Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of medical
devices, in collaboration with the European Committee for Standardization (CEN) Technical Committee
CEN/TC 206, Biocompatibility of medical and dental materials and devices, in accordance with the Agreement
on technical cooperation between ISO and CEN (Vienna Agreement).
A list of all parts in the ISO 10993 series can be found on the ISO website.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv
ISO 10993-4:2017/PRF Amd 1(en)
Biological evaluation of medical devices — —
Part 4:
Selection of tests for interactions with blood — Amendment
AMENDMENT 1
3.4
Replace “ISO/TR 10993-20” with “ISO/TS 10993-20” in Note 1 to entry.
5.2.2
Replace the subclause heading with the following:
5.2.2 External communicating devices indirectly contacting blood
Delete the following bullet points “cannulae”, “cell savers””, “intravascular catheters”,” and “blood collection
devices”.
Replace “blood and blood product” with “saline and/or therapeutics” to readas follows:
— devices for the storage and administration of either saline and/or therapeutics, or both (e.g. tubing
and bags);
Add the bullet point “- “blood monitors with indirect blood contact.”” as the second bullet point.
5.2.3
Add “blood collection devices” as a second bullet point, “cannulae” as a fourth bullet point, “cell savers” as a
sixth bullet point and “devices for the storage and administration of blood and blood products (e.g. tubing and
bags)” as an eighth bullet point.
Delete “or indirect” in the third bullet point to readas follows:
— blood monitoring devices with direct blood contact;
ISO 10993-4:2017/PRF Amd 1(en)
6.1.2
Add the following text to the second paragraph after the sentence “Only direct or indirect blood-contacting
parts should be tested.” the following sentences:.”:
For direct contact haemocompatibility testing (e.g. direct haemolysis, complement activation, coagulation,
platelet activation, haematology, in vitro/ or ex vivo thrombosis), testing should be conducted using only
the direct blood contacting components of the device to minimize interference of non-direct blood
contacting components on the results. For extract-based haemocompatibility testing (e.g. indirect
haemolysis), testing should be conducted using only the direct and indirect blood-contacting components
of the device. The test article shall be described, and a justification shall be provided if the test article
includes device components that include different tissue contact than described above.
RemoveReplace the fourth paragraph and replace with:
As many tests for haemocompatibility are recognized to be generally surface-contact dependent (e.g.
direct contact haemolysis, complement activation, coagulation, platelet activation, haematology, and in
vitro/ or ex vivo thrombosis)), such tests willdo not apply to indirect contact applications. For externally
communicating medical devices or components that have indirect blood contact, generally only an
indirect contact haemolysis test is generally recommended.
6.1.4
ChangeReplace NOTE 1 to readwith:
NOTE 1 Changes in the manufacturing process (e.g. change in manufacturer,), the use of different manufacturing
aids that can affect the surface properties, or the chemistry of the complete sterilized device, can also impact
haemocompatibility.
6.1.6
Replace Table 1 with:
ISO 10993-4:2017/PRF Amd 1(en)
Table 1 — Devices or device components and categories of appropriate testing for consideration
Test category
c
Thrombosis
Haemolysis
Device examples
In vitro
In vivo/
or
d
Complement
Material-induced Mechanically-induced Coagulation Platelet activation Haematology a
ex vivo
d
Complement
e
External communicating devices indirectly contacting blood
Blood monitors with indirect blood contact X
Devices for storage and administration of saline and/or therapeutics (e.g. tubing
X
and bags), extension sets
b
External communicating devices directly contacting circulating blood
Blood collection devices X X X X
f
Blood administration sets and extension sets X X X X X
Catheters in place for less than 24 h (e.g. atherectomy devices, intravascular
ultrasound catheters, antegrade/ or retrograde coronary perfusion catheters, X X X X X
guide wires); cannulae
Catheters in place for more than 24 h (e.g. parenteral nutrition catheters, central
X X X X X
venous catheters); cannulae
Cell savers X X X X
Devices for adsorption of specific substances from blood X X X X X
Donor and therapeutic aphaeresis equipment and cell separation systems X X X X X
Cardiopulmonary bypass system and components X X X X X X X
Haemodialysis/ or haemofiltration equipment X X X X X X X
Leukocyte removal filter X X X X X X
Percutaneous circulatory support devices X X X X X X X
Implant devices
Annuloplasty rings, mechanical heart valves X X X
Embolization devices X X
ISO 10993-4:2017/PRF Amd 1(en)
Test category
c
Thrombosis
Haemolysis
Device examples
In vitro
In vivo/
or
d
Complement
a
Material-induced Mechanically-induced Coagulation Platelet activation Haematology
ex vivo
d
Complement
Endovascular grafts X X
Implantable defibrillator and cardioverter leads X X
Intra-aortic balloon pumps X X X
Pacemaker leads X X
Prosthetic (synthetic) vascular grafts and patches, including arteriovenous
X X
shunts
Stents (vascular) X X
Tissue heart valves, vascular grafts and patches and AV shunts X X
Total artificial hearts X X X
Vena cava filters X X
Ventricular-assist devices X X X
a
Thrombosis is an in vivo or ex vivo phenomenon but can be simulated with in vitro conditions. In vivo or ex vivo testing might not be necessary if clinically relevant in vitro thrombosis testing is
performed.
b
Some examples here may contain other components with indirect blood contact. For device components that only have indirect blood contact, direct contact material-induced haemolysis, mechanical
haemolysis, thrombosis, and complement activation mayare not bealways necessary. For components with indirect blood contact, generally only an indirect contact haemolysis test is recommended.
c
It is recognized that coagulation, platelet, and leucocyte responses are primarily involved in the process of thrombosis. Therefore, in vitro thrombogenicity methods can be acceptable in place of in vivo
testing if scientifically justified. The manufacturer should justify which specific testing in the coagulation, platelet and haematology test categories is appropriate for their devices.
d
Complement activation testing is also requested by certain regulatory authorities to address other end points such as anaphylaxis for all devices with direct blood contact.
e
Except for devices composed of novel materials, each test in the category of thrombosis is generally not necessary for indirect blood contact devices.
f
For blood administration sets without using mechanical pumps, mechanically induced haemolysis testing is generally not necessary.
ISO 10993-4:2017/PRF Amd 1(en)
6.1.11
Delete “(see also ISO 10993--2)” at the end of the second paragraph.
6.1.12
Replace the paragraph with the following:
The use of antithrombotics in in vivo and ex vivo tests should be avoided unless the device is designed to
perform in their presence. Even if the device is designed to perform in their presence, the completion of
studies without antithrombotics maycan also be required in order to properly assess the thrombosis risk
to patients that cannot receive antithrombotics. The type and concentration of antithrombotic(s) used
influence(s) blood/device interactions and their selection shall be justified. Devices that are used with
antithrombotics should be assessed using them in the range of concentrations specified clinically and/or
described in the product IFU or other appropriate literature. Species differences should also be
considered when determining the appropriate level of antithrombotic(s).
Add the following NOTE at the end of this paragraph:
NOTE Antithrombotics maycan consist of any combination of either antiplatelet drugs (e.g.,. acetylsalicylic acid,
clopidogrel, and glycoprotein IIb/IIIa receptor antagonists) and/or anticoagulants (e.g. unfractionated or low
molecular weight heparin, warfarin, and direct thrombin inhibitors).), or both.
6.1.14
Delete "see ISO 10993-2" and add the following NOTE after the paragraph:
NOTE For more information on animal welfare, see ISO 10993-2.
6.3.1
Replace “Alternatives to the latter may be feasible if validated.” bywith:
The use of blood older than 4 h may be feasible for certain tests, if validated alongside fresh-freshly
obtained blood or by other scientifically sound methods.
A.1.1
Delete “of non-contact-, externally communicating and implant devices.” and have simpler” from the sentence
end withas follows: “and a list of tests for evaluating blood/device interactions. “.”
ISO 10993-4:2017/PRF Amd 1(en)
A.1.4
Replace the first sentence of the third paragraph with the following:
[43] [193][194][195][199 ][200][203]
The classical Chandler loop in vitro test model or modifications thereof ] are
examples of models used to test for general material/ or device haemocompatibility under physiological
and/or quasi-physiological flow conditions.
Add the following sentence at the end of the third paragraph:
Recent publications that describe and apply alternative in vitro methods are References [243–] to [249].
Clause A.3
Add “(or an alternative surface treatment intended to have anti-thrombotic properties)” in the second
sentence of the second paragraph to readas follows:
For example, following simple dose-response kinetics, the thromboresistance of a medical device heparin
coating (or an alternative surface treatment intended to have anti-thrombotic properties) can be
completely masked by normal (clinical) levels of solution heparin anticoagulant.
Replace the third sentence with the following:
However, under a reduced/challenging level of solution heparin or in a non-anticoagulated model, the
effectiveness of the heparin coating (or alternative anti-thrombotic surface treatment) to reduce
thrombus formation becomes more apparent.
Bibliography
Add the following references:
1)
[238] ISO 10993-2, Biological evaluation of medical devices — Part 2: Animal welfare requirements
[239] ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after
imp
...
Norme
internationale
ISO 10993-4
Troisième édition
Évaluation biologique des
2017-04
dispositifs médicaux —
AMENDEMENT 1
Partie 4:
Choix des essais pour les
interactions avec le sang
AMENDEMENT 1
Biological evaluation of medical devices —
Part 4: Selection of tests for interactions with blood
AMENDMENT 1
PROOF/ÉPREUVE
Numéro de référence
ISO 10993-4:2017/Amd.1:2024(fr) © ISO 2024
Norme
ISO 10993-4:2017/Amd.1:2024(fr)
internationale
ISO 10993-4
Troisième édition
Évaluation biologique des
2017-04
dispositifs médicaux —
Partie 4: AMENDEMENT 1
Choix des essais pour les
interactions avec le sang
AMENDEMENT 1
Biological evaluation of medical devices —
Part 4: Selection of tests for interactions with blood
AMENDMENT 1
DOCUMENT PROTÉGÉ PAR COPYRIGHT
© ISO 2024
Tous droits réservés. Sauf prescription différente ou nécessité dans le contexte de sa mise en œuvre, aucune partie de cette
publication ne peut être reproduite ni utilisée sous quelque forme que ce soit et par aucun procédé, électronique ou mécanique,
y compris la photocopie, ou la diffusion sur l’internet ou sur un intranet, sans autorisation écrite préalable. Une autorisation peut
être demandée à l’ISO à l’adresse ci-après ou au comité membre de l’ISO dans le pays du demandeur.
ISO copyright office
Case postale 401 • Ch. de Blandonnet 8
PROOF/ÉPREUVE
CH-1214 Vernier, Genève
Tél.: +41 22 749 01 11
E-mail: copyright@iso.org
Web: www.iso.org
Publié en Suisse Numéro de référence
ISO 10993-4:2017/Amd.1:2024(fr) © ISO 2024
PROOF/ÉPREUVE
ii
ISO 10993-4:2017/Amd.1:2024(fr)
Avant-propos
L’ISO (Organisation internationale de normalisation) est une fédération mondiale d’organismes nationaux
de normalisation (comités membres de l’ISO). L’élaboration des Normes internationales est en général
confiée aux comités techniques de l’ISO. Chaque comité membre intéressé par une étude a le droit de faire
partie du comité technique créé à cet effet. Les organisations internationales, gouvernementales et non
gouvernementales, en liaison avec l’ISO participent également aux travaux. L’ISO collabore étroitement avec
la Commission électrotechnique internationale (IEC) en ce qui concerne la normalisation électrotechnique.
Les procédures utilisées pour élaborer le présent document et celles destinées à sa mise à jour sont
décrites dans les Directives ISO/IEC, Partie 1. Il convient, en particulier, de prendre note des différents
critères d’approbation requis pour les différents types de documents ISO. Le présent document
a été rédigé conformément aux règles de rédaction données dans les Directives ISO/IEC, Partie 2
(voir www.iso.org/directives).
L’ISO attire l’attention sur le fait que la mise en application du présent document peut entraîner l’utilisation
d’un ou de plusieurs brevets. L’ISO ne prend pas position quant à la preuve, à la validité et à l’applicabilité
de tout droit de propriété revendiqué à cet égard. À la date de publication du présent document, l’ISO
n’avait pas reçu notification qu’un ou plusieurs brevets pouvaient être nécessaires à sa mise en application.
Toutefois, il y a lieu d’avertir les responsables de la mise en application du présent document que des
informations plus récentes sont susceptibles de figurer dans la base de données de brevets, disponible à
l’adresse www.iso.org/brevets. L’ISO ne saurait être tenue pour responsable de ne pas avoir identifié tout ou
partie de tels droits de brevet.
Les appellations commerciales éventuellement mentionnées dans le présent document sont données pour
information, par souci de commodité, à l’intention des utilisateurs et ne sauraient constituer un engagement.
Pour une explication de la nature volontaire des normes, la signification des termes et expressions
spécifiques de l’ISO liés à l’évaluation de la conformité, ou pour toute information au sujet de l’adhésion
de l’ISO aux principes de l’Organisation mondiale du commerce (OMC) concernant les obstacles techniques
au commerce (OTC), voir www.iso.org/avant-propos.
Le présent document a été élaboré par le comité technique ISO/TC 194, Évaluation biologique et clinique
des dispositifs médicaux, en collaboration avec le comité technique CEN/TC 206, Évaluation biologique et
clinique des dispositifs médicaux, du Comité européen de normalisation (CEN), conformément à l’Accord de
coopération technique entre l’ISO et le CEN (Accord de Vienne).
Une liste de toutes les parties de la série ISO 10993 se trouve sur le site web de l’ISO.
Il convient que l’utilisateur adresse tout retour d’information ou toute question concernant le présent
document à l’organisme national de normalisation de son pays. Une liste exhaustive desdits organismes se
trouve à l’adresse www.iso.org/fr/members.html.
PROOF/ÉPREUVE
iii
ISO 10993-4:2017/Amd.1:2024(fr)
Évaluation biologique des dispositifs médicaux —
Partie 4:
Choix des essais pour les interactions avec le sang
AMENDEMENT 1
3.4
Remplacer «ISO/TR 10993-20» par «ISO/TS 10993-20» dans la Note 1 à l’article.
5.2.2
Remplacer le titre du paragraphe par:
5.2.2 Dispositifs communiquant avec l’extérieur qui sont en contact indirect avec le sang
Supprimer les points de liste: «canules», «systèmes “cell savers” (système de récupération de sang
périopératoire)», «cathéters intravasculaires» et «dispositifs de prélèvement sanguin».
Remplacer «de sang et de produits sanguins» par «de solution saline et/ou traitements» comme suit:
— dispositifs de stockage et de perfusion de solution saline ou de traitements, ou des deux (par exemple
tubes et sacs);
Ajouter le point «moniteurs sanguins en contact indirect avec le sang» comme second point de liste.
5.2.3
Ajouter «dispositifs de prélèvement sanguin» en deuxième point, «canules» en quatrième point, «systèmes
“cell savers” (système de récupération de sang périopératoire)» en sixième point et «dispositifs de stockage
et de transfusion de sang et de produits sanguins (par exemple, tubes et sacs)» en huitième point.
Supprimer «ou indirect» dans le troisième point comme suit:
— moniteurs sanguins en contact direct avec le sang;
6.1.2
Ajouter le texte suivant au deuxième alinéa, après la phrase «Il convient de ne soumettre à essai que les
parties en contact direct ou indirect avec le sang.», les phrases suivantes:
Pour les essais d’hémocompatibilité par contact direct (par exemple hémolyse directe, activation du
complément, coagulation, activation plaquettaire, hématologie, thrombose in vitro ou ex vivo), il convient
de réaliser les essais en n’utilisant que les composants en contact direct avec le sang du dispositif afin
de réduire le plus possible l’interférence des composants n’ayant aucun contact direct avec le sang sur
les résultats. Pour les essais d’hémocompatibilité à partir d’extraits (par exemple hémolyse indirecte), il
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(fr)
convient de réaliser les essais en n’utilisant que les composants en contact direct et indirect avec le sang
du dispositif. Le spécimen d’essai doit être décrit et une justification doit être fournie si le spécimen d’essai
comprend des composants de dispositif avec un contact tissulaire différent de celui décrit ci-dessus.
Remplacer le quatrième alinéa par:
Puisque de nombreux essais d’hémocompatibilité sont considérés comme étant généralement
dépendants de la surface de contact, ces essais (par exemple hémolyse par contact direct, activation
du complément, coagulation, activation plaquettaire, hématologie et thrombose in vitro ou ex vivo) ne
concernent pas les applications à contact indirect. Pour les dispositifs médicaux communiquant avec
l’extérieur ou les composants ayant un contact indirect avec le sang, il est généralement recommandé de
ne procéder qu’à un essai d’hémolyse par contact indirect.
6.1.4
Remplacer la NOTE 1 par:
NOTE 1 Les changements dans le procédé de fabrication (par exemple un changement de fabricant),
l’utilisation d’auxiliaires de fabrication pouvant avoir une incidence sur les propriétés de surface ou sur les
caractéristiques chimiques du dispositif stérilisé complet, sont également susceptibles d’affecter l’hémo-
compatibilité.
6.1.6
Remplacer le Tableau 1 par:
Tableau 1 — Dispositifs ou composants de dispositifs et catégories d’essais appropriées à considérer
Catégorie d’essai
c
Hémolyse Thrombose
In vitro
In
Exemples de dis-
vivo
positifs Induite Induite mécani-
ou
par des quement Activation
d
Coagulation Complément Hématologie
ex
maté- plaquettaire
a
vivo
riaux
e
Dispositifs communiquant avec l’extérieur qui sont en contact indirect avec le sang
Moniteurs sanguins
en contact indirect X
avec le sang
a
La thrombose est un phénomène in vivo ou ex vivo, mais peut être simulée dans des conditions in vitro. Les essais in vivo ou ex
vivo peuvent ne pas être nécessaires si des essais de thrombose in vitro cliniquement pertinents sont réalisés.
b
Certains des exemples ci-dessus peuvent contenir d’autres composants en contact indirect avec le sang. Pour les composants
du dispositif qui ne sont qu’en contact indirect avec le sang, l’hémolyse par contact direct avec le matériau, l’hémolyse mécanique,
la thrombose et l’activation du complément ne sont pas toujours nécessaires. Pour les composants en contact indirect avec le
sang, il est généralement recommandé de ne procéder qu’à un essai d’hémolyse par contact indirect.
c
Il est admis que les réponses en termes de coagulation, plaquettaire et leucocytaire sont principalement impliquées dans le
processus de thrombose. Par conséquent, les méthodes de thrombogénicité in vitro peuvent être acceptables à la place des essais
in vivo si elles sont scientifiquement justifiées. Il convient que le fabricant justifie quels essais spécifiques dans les catégories
d’essais de coagulation, d’activation plaquettaire et d’hématologie sont appropriés pour leurs dispositifs.
d
Un essai d’activation du complément est également demandé par certaines autorités de réglementation pour traiter d’autres
points finaux tels que l’anaphylaxie pour tous les dispositifs en contact direct avec le sang.
e
Il n’est généralement pas nécessaire d’effectuer chacun des essais de la catégorie «thrombose» pour les dispositifs en contact
indirect avec le sang, sauf pour les dispositifs composés de matériaux nouveaux.
f
L’essai d’hémolyse induite mécaniquement n’est généralement pas nécessaire pour les ensembles de transfusion sanguine
qui n’utilisent pas de pompe mécanique.
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(fr)
TTabableleaauu 1 1 ((ssuuiitte)e)
Catégorie d’essai
c
Hémolyse Thrombose
In vitro
In
Exemples de dis-
vivo
positifs
Induite Induite mécani-
ou
par des quement Activation
d
Coagulation Complément Hématologie
ex
maté- plaquettaire
a
vivo
riaux
Dispositifs de stoc-
kage et de perfusion
de solution saline
et/ou de traite-
X
ments (par exemple
tubes et sacs),
ensembles d’exten-
sion
b
Dispositifs communiquant avec l’extérieur qui sont en contact direct avec le sang circulant
Dispositifs de prélè-
X X X X
vement sanguin
Ensembles de trans-
fusion sanguine et
f
X X X X X
ensembles d’exten-
sions
Cathéters en place
pendant moins de
24 h (par exemple
dispositifs d’athé-
rectomie, cathéters
intravasculaires à X X X X X
ultrasons, cathéters
de perfusion coro-
naire antérograde
ou rétrograde,
guides); canules
Cathéters en place
pendant plus de
24 h (par exemple
cathéters de nutri- X X X X X
tion parentérale,
cathéters veineux
centraux); canules
a
La thrombose est un phénomène in vivo ou ex vivo, mais peut être simulée dans des conditions in vitro. Les essais in vivo ou ex
vivo peuvent ne pas être nécessaires si des essais de thrombose in vitro cliniquement pertinents sont réalisés.
b
Certains des exemples ci-dessus peuvent contenir d’autres composants en contact indirect avec le sang. Pour les composants
du dispositif qui ne sont qu’en contact indirect avec le sang, l’hémolyse par contact direct avec le matériau, l’hémolyse mécanique,
la thrombose et l’activation du complément ne sont pas toujours nécessaires. Pour les composants en contact indirect avec le
sang, il est généralement recommandé de ne procéder qu’à un essai d’hémolyse par contact indirect.
c
Il est admis que les réponses en termes de coagulation, plaquettaire et leucocytaire sont principalement impliquées dans le
processus de thrombose. Par conséquent, les méthodes de thrombogénicité in vitro peuvent être acceptables à la place des essais
in vivo si elles sont scientifiquement justifiées. Il convient que le fabricant justifie quels essais spécifiques dans les catégories
d’essais de coagulation, d’activation plaquettaire et d’hématologie sont appropriés pour leurs dispositifs.
d
Un essai d’activation du complément est également demandé par certaines autorités de réglementation pour traiter d’autres
points finaux tels que l’anaphylaxie pour tous les dispositifs en contact direct avec le sang.
e
Il n’est généralement pas nécessaire d’effectuer chacun des essais de la catégorie «thrombose» pour les dispositifs en contact
indirect avec le sang, sauf pour les dispositifs composés de matériaux nouveaux.
f
L’essai d’hémolyse induite mécaniquement n’est généralement pas nécessaire pour les ensembles de transfusion sanguine
qui n’utilisent pas de pompe mécanique.
PROOF/ÉPREUVE
ISO 10993-4:2017/Amd.1:2024(fr)
TTabableleaauu 1 1 ((ssuuiitte)e)
Catégorie d’essai
c
Hémolyse Thrombose
In vitro
In
Exemples de dis-
vivo
positifs
Induite Induite mécani-
ou
par des quement Activation
d
Coagulation Complément Hématologie
ex
maté- plaquettaire
a
vivo
riaux
Systèmes «cell
savers» (système
de récupération X X X X
de sang périopéra-
toire)
Dispositifs d’ad-
sorption de subs-
X X X X X
tances sanguines
spécifiques
Équipement d’aphé-
rèse donneur et
thérapeutique et X X X X X
systèmes de sépara-
tion cellulaire
Système de circula-
tion extracorporelle X X X X X X X
et composants
Équipement
d’hémodialyse ou X X X X X X X
d’hémofiltration
Filtre leucocytaire X X X X X X
Dispositifs percu-
tanés d’assistance X X X X X X X
circulatoire
Dispositifs implantés
Anneaux d’annulo-
plastie, valves car- X X X
diaques mécaniques
Dispositifs d’embo-
X X
lisation
Greffes endovascu-
X X
laires
a
La thrombose est un phénomène in vivo ou ex vivo, mais peut être simulée dans des conditions in vitro. Les essais in vivo ou ex
vivo peuvent ne pas être nécessaires si des essais de thrombose in vitro clinique
...
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